Rituximab in Children with Steroid-Dependent Nephrotic Syndrome

Abstract

Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1-16 years who had developed SDNS in the previous 6-12 months and were maintained in remission with high prednisone doses ($0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m 2 ; intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m 2 per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for $1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6-13.5 years]) were enrolled and followed for #60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS.

Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children

“…The steroids were tapered and withdrawn in the following month in both groups. Patients treated with rituximab (375 mg/m 2 ) completed steroid withdrawal as indicated earlier; 80% of these patients maintained drug-free remission at 1 year, whereas patients who did not receive rituximab had recurrence of proteinuria shortly after steroid elimination (27). The median relapse-free survival time after repeated rituximab infusions in the follow-up study of this trial cohort was 18 months (95% confidence interval, 9 to 32 months).…”

“…Between 2011 and 2015, five clinical trials on the use of rituximab in idiopathic nephrotic syndrome were reported: four as journal articles (27)(28)(29)(30) and one in abstract form. Results of four prospective studies were also published in the same period (see below) (27,31,32).…”

“…Results of four prospective studies were also published in the same period (see below) (27,31,32). All these trials tested the effects of rituximab as steroid-sparing agent.…”

“…Tables 2 and 3 summarize the key characteristics and findings from these randomized controlled trials. One trial enrolled children with idiopathic nephrotic syndrome maintained in remission with high-dose steroids alone (27), three trials enrolled children maintained in remission with steroids and calcineurin inhibitors (28,29), and one trial assessed the effect of rituximab in children with nephrotic syndrome resistant to both steroids and calcineurin inhibitors (30). Figure 2 presents a flow chart of treatment of idiopathic nephrotic syndrome based on randomized controlled trials.…”

“…In one trial, children who were dependent on high-dose steroids (at least 0.7 mg/kg per day) were randomly assigned to continue steroids alone or receive a single intravenous pulse of rituximab (375 mg/m 2 ) in addition to steroids (27). The steroids were tapered and withdrawn in the following month in both groups.…”